Dynamic structural determinants underlie the neurotoxicity of the N-terminal tau 26-44 peptide in Alzheimer's disease and other human tauopathies

Giordano Perini, Gabriele Ciasca*, Eleonora Minelli, Massimiliano Papi, Valentina Palmieri, Giuseppe Maulucci, Matteo Nardini, Valentina Latina, Veronica Corsetti, Fulvio Florenzano, Pietro Calissano, Marco De Spirito, Giuseppina Amadoro

*Autore corrispondente per questo lavoro

Risultato della ricerca: Contributo in rivistaArticolo in rivista

8 Citazioni (Scopus)

Abstract

The intrinsically disordered tau protein plays a pivotal role in the pathogenesis of Alzheimer's disease (AD) and other human tauopathies. Abnormal post-translational modifications of tau, such as truncation, are causally involved in the onset/development of these neurodegenerative diseases. In this context, the AD-relevant N-terminal fragment mapping between 26 and 44 amino acids of protein (tau26-44) is interesting, being endowed with potent neurotoxic effects in vitro and in vivo. However, the understanding of the mechanism(s) of tau26-44 toxicity is a challenging task because, similarly to the full-length tau, it does not have a unique 3D structure but exists as dynamic ensemble of conformations. Here we use Atomic Force Spectroscopy, Small Angle X-ray Scattering and Molecular Dynamics simulation to gather structural and functional information on the tau26-44. We highlight the presence, the type and the location of its temporary secondary structures and we unveil the occurrence of relevant transient tertiary conformations that could contribute to tau26-44 toxicity. Data are compared with those obtained on the biologically-inactive, reverse-sequence (tau44-26 peptide) which has the same mass, charge, aminoacidic composition as well as the same overall unfolded character of tau26-44.
Lingua originaleEnglish
pagine (da-a)278-289
Numero di pagine12
RivistaInternational Journal of Biological Macromolecules
Volume141
DOI
Stato di pubblicazionePubblicato - 2019

Keywords

  • Alzheimer Disease
  • Alzheimer's disease (AD)
  • Amino Acid Sequence
  • Animals
  • Atomic Force Microscopy (AFM)
  • Humans
  • Microscopy, Atomic Force
  • Molecular Dynamics (MD) simulation
  • Molecular Dynamics Simulation
  • Neurons
  • Peptides
  • Protein Conformation
  • Rats
  • Small Angle X-ray Scattering (SAXS)
  • Structure-Activity Relationship
  • Tau protein
  • Tauopathies
  • X-Ray Diffraction
  • tau Proteins

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